Age related osteoporotic fractures are largely due to an increased propensity to fall with aging and a reduction in bone strength. Although skeletal architecture contributes to fracture risk, bone mineral density (BMD) is a critical determinant of bone strength and fracture risk. Between 60 and 80% of the variance in peak bone mineral density of adults is genetic. Osteoporosis in later life is a function of peak bone mass attained during young adulthood and rate of loss. During the tenure of the current award we have identified several highly promising chromosomal regions that contain genes that influence peak bone strength in men and women. This project will focus on three chromosomal regions where linkage data in both humans and animal models indicate that these regions harbor genes that affect peak BMD. The goals of this study are to identify these genes using a combined positional cloning/candidate approach in a well-characterized population of men and women. Identification of these genes may: 1) lead to molecular tests that predict osteoporosis risk and allow institution of early preventive measures; 2) provide insight into basic bone cell biology and other factors that affect peak BMD and predispose to osteoporosis; and 3) provide molecular targets for therapeutic agents to influence BMD.